PB1903: TRIAL IN PROGRESS: A MULTICENTER, OPEN-LABEL, PHASE IB/II STUDY TO DETERMINE THE DOSE AND SAFETY OF ASCIMINIB IN PEDIATRIC PATIENTS WITH CHRONIC MYELOID LEUKEMIA IN CHRONIC PHASE (CML-CP)
Authors: N. Hijiya, S. Kapoor, M. Hoch, L. Descamps, M. A. Bayar, N. Ramscar
Journal: HemaSphere (2022)

Background: Tyrosine kinase inhibitors (TKIs) are the standard of care for adult and pediatric patients (pts) with CML-CP. Five TKIs are approved for adults: imatinib, dasatinib, nilotinib, bosutinib, and ponatinib. However, only imatinib, dasatinib, and nilotinib are approved for pediatric pts. Efficacy and safety profiles of TKIs are similar in adult and pediatric pts; however, growth retardation has been reported in the pediatric population, in whom long-term adverse effects are unknown. Therefore, safer and more efficacious options are needed for pediatric pts. Asciminib is a recently approved drug that inhibits BCR::ABL1 by Specifically Targeting the ABL Myristoyl Pocket (STAMP). In the phase III ASCEMBL trial for adults with heavily pretreated CML-CP, asciminib (40 mg twice daily [BID]) had an improved major molecular response rate (25.5% vs 13.2%) at week 24 and a better safety profile compared with bosutinib (500 mg once daily). Here we present the phase Ib/II trial evaluating asciminib in pediatric pts. Aims: The primary objectives of this study are to characterize the pharmacokinetic (PK) profile of asciminib in pediatric pts and identify a pediatric formulation dose leading to an asciminib exposure comparable to the adult dose, 40 mg BID. Methods: This is a multicenter, open-label study (NCT04925479). Eligible pts have Philadelphia chromosome–positive CML-CP treated with ≥1 prior TKI, do not have a T315I mutation, and are aged ≥1 to <18 years, provided informed consent. Adolescent pts aged ≥14 to <18 years and weighing ≥40 kg will be enrolled in the exploratory adult formulation group, receiving the adult dose, until the pediatric formulation is available. In part 1 (dose-determining cohort), 4 to 6 pts aged ≥1 to <18 years will receive the pediatric formulation (body weight–adjusted dose of asciminib taken with food) to obtain ≥4 participants evaluable for PK data. This evaluation will determine whether median exposure in pediatric pts is comparable to asciminib 40 mg BID taken without food in adult pts. PK and safety will be assessed during the first 28 days after treatment initiation. In part 2 (expansion cohort), the body weight–adjusted dose determined in part 1 will be used, and the total pts enrolled on pediatric formulation will be increased to 30, including those from part 1 (15 pts aged 1 to <12 years and 15 pts aged 12 to <18 years). Pts receiving the adult formulation may switch to the pediatric formulation in part 2 but will not be counted toward the 30 pts enrolled in part 2. A 2nd interim PK and safety analysis will be conducted after all pts in part 2 have completed 28 days of treatment. The total duration of the study treatment period is 5 years (Figure). The primary PK endpoints, safety, and pharmacodynamics will be assessed after all pts have been on study for 52 weeks or discontinued earlier. After all pts have been on study for 5 years or discontinued earlier, a final analysis will be performed. Pts who discontinue the study early will be followed up for survival until the study is complete. Results: The primary endpoints include PK parameters. Secondary endpoints include hematologic and molecular responses, safety, acceptability, and palatability of asciminib. Image:Summary/Conclusion: Data from this study will be used to provide a pediatric dose and support a strategy of full extrapolation from adult data to use in the pediatric setting.